Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes

Huang Hui, Winter, Wang Huajun, Weinstock, Xing Heming, Goodstadt Leo, Stenson, Cooper, Smith Douglas, Albà, Ponting, Fechtel Kim

Description

Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change. Results Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences are revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discriminated between disease and non-disease genes, synonymous substitution rates are significantly higher for disease genes. In neurological and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological and pulmonary disease systems have changed more rapidly. Amino-acid substitutions associated with human inherited disease occur at sites that are more highly conserved than the average; nevertheless, 15 substituting amino acids associated with human disease were identified as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion disease genes were found to contain substantially fewer of such repeats. Six human genes that share the same characteristics as triplet repeat-expansion disease-associated genes were identified; although four of these genes are expressed in the brain, none is currently known to be associated with disease. Conclusions Most human disease genes have been retained in rodent genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human neurological disease are likely to most faithfully represent human disease processes. However, with regard to neurological triplet repeat expansion-associated human disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo .

Informations

• Publié par: biomed
• Publié le: 01 janvier 2004
• Nombre de lectures: 9
• Langue: English

Extrait

2eVH R t0 oual e 0alu.4 s nmg e e a 5 r , c Is h sue 7, Article R47 Open Access Evolutionary conservation and se lection of human disease gene orthologs in the rat and mouse genomes Hui Huang * , Eitan E Winter  , Huajun Wang * , Keith G Weinstock * , Heming Xing * , Leo Goodstadt  , Peter D Stenson  , David N Cooper  , Douglas Smith §¶ , M Mar Albà ¥ , Chris P Ponting  and Kim Fechtel * Addresses: * Department of Bioinformatics, Genome Therapeutics Corporation, Waltham, MA 02453, USA.  MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.  Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. § Genome Sequencing Center, Genome Therapeutics Corporation, Waltham, MA 02453, USA. ¶ Agencourt Bioscience Corporation, Beverly, MA 01915, USA. ¥ Grup de Recerca en Informàtica Biomèdica, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain. Correspondence: Kim Fechtel. E-mail: [e-mail]

Published: 2 8 June 2004 Received: 16 March 2004 Genome Biology 2004, 5: R47 R A e c v c i e s p e t d e :  d 1 :  0 2   8 M   a M y a   y 2   0 2 0 0 4 04 The electronic version of this arti cle is the complete one and can be found online at http://genomebiology.com/2004/5/7/R47 © 2004 Huang et al .; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitt ed in all media for any purpose, provided this notice is preserved along with the article's original URL. t<Edamhirpviseyto>e   ldtcaMue h stv e aoi   oendcgln o g e laen pmr<oeymprs/ r gcepdeaoni>h n tf efioe s nefrmsr   niss v iea gehtw n i a iotnvfrniv e c   ec a stot n imtdngl teysar nteifilbtr e o ucntt m ei o o d ft   hnats lheuo i tefbri    se r hts o ua. d nmT e thai n ae t nl    la o dyv r i t as h oiel o a o l sbu o eir g  l ig s ut  eyo n w f idoegtf  e hort nsh r t e ha s h onpaludesoicsmgnto sagt c n i oon ,atf  t thmtee h doi e r uw   resoiae t vti  heo a rl n hoa d ulg,l   y m l eoavf o n eus hltd s  ui erso emegfc a e cso n  eotn.dl simyHse, r e tsvarhs e ae,t   i rwo a sten   giwa e n vnldleo   stamthsi e ghi a srt evreiq anuwt e gh snae osctfseh is e s rvtn o ehldw u   twmipioeat n rh -   Abstract Background: Model organisms have contributed substantially to our under standing of the etiology of human disease as well as having assisted with the development of new treatment moda lities. The availability of the human , mouse and, most recently, the rat genome sequences now permit the comp rehensive investigation of the rodent or thologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from th eir rodent orthologs with respect to thei r overall levels of conservation and their rates of evolutionary change. Results: Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences ar e revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discrimina ted between disease and non-disease genes, synonymous substitution rates are signific antly higher for disease genes. In neurol ogical and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological an d pulmonary disease systems have changed more rapidly. Amino-acid substitu tions associated with human inherited dise ase occur at sites that are more highly conserved than the average; neve rtheless, 15 substituting amino acids associated with human disease were identified as wild- type amino acids in the rat. Rodent orthologs of human trin ucleotide repeat-expansion diseas e genes were found to contain substantially fewer of such repeats. Six human genes that shar e the same characteristics as tr iplet repeat-expansion disease- associated genes were identified ; although four of these genes are expressed in the brain, none is currently known to be associated with disease. Conclusions: Most human disease genes have been retained in rode nt genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a find ing that may reflect increased mutation rate s in the chromosomal regions in which dise ase genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human ne urological disease are likely to most fait hfully represent human disease processes. However, with regard to neurol ogical triplet repeat expansion-associated hu man disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat expansions. The iden tification of six genes in th is study that have multiple characteristics associated with repeat expansion-di sease genes raises the po ssibility that not all huma n loci capable of facilitating neurological disease by repeat expa nsion have as yet been identified.

Genome Biology 2004, 5: R47